3,4-Methylenedioxymethamphetamine ("Ecstasy;" MDMA) is rapidly becoming a problem of monumental proportions. Its current popularity is inextricably linked to its use at all night dance parties called "raves," at which the drug is taken to produce euphoria, energy, and a desire to socialize. Although the drug has developed the reputation as a "safe" drug, several studies in rats and humans have established unequivocally that MDMA induces a myriad of deleterious effects, including a variety of psychopathological states. Although it is well documented that MDMA induces a variety of untoward effects, including death, the stark reality is that the underlying biochemical mechanisms by which it elicits these effects have not been fully elucidated. The current dogma is that the neurotoxicity induced by MDMA must be occassioned by metabolites, because intracerebroventricular injections of MDMA into rat brains do not produce the destruction of neurons, particularly serotonergic neurons, as is the case when the drug is administered orally to both rats and humans. The proposed project seeks to enhance the existing body of knowledge on the underlying biochemical mechanisms by which MDMA elicits its neurotoxicity. Toward this end, several potential metabolites of MDMA will be synthesized and evaluated, primarily to assess their propensity to induce neurotoxicity, using rats and a variety of cell lines. These potential metabolites will be primarily a variety of thioether conjugates of MDMA and analogues thereof, 6-hydroxy-alpha-methyldopamine and analogues thereof, and aminochrome derivatives. Furthermore, the project seeks to develop potential antagonists of MDMA. Toward this end, numerous bulky N-alkyl or N-aralkyl analogues of amphetamine, methylenedioxyamphetamine, and p-chloroamphetamine will be synthesized and evaluated for their ability to attenuate the effects of MDMA in rats and various cell lines. It is postulated that the results garnered from these studies will facilitate the elucidation of the molecular processes associated with the neurotoxicity induced by MDMA.